Interleukin-6 (IL-6) is a multifunctional cytokine produced in macrophages, fibroblasts and other cell types. It is known that a number of stimuli induce IL-6 secretion in different target cells including cytokines, bacteria and bacterial products and certain viruses. In the present study, we have found that HIV induces high-level IL-6 secretion in human monocytes. This effect requires monocyte/macrophage infection with HIV because it is not observed in the presence of heat-inactivated HIV. In addition, IL-6 production is first detected 8-12 days after monocyte infection, at a time when reverse transcriptase levels begin to climb. Because HIV induces IL-6 production in vitro, we have examined the possibility that IL-6 levels might be elevated in HIV-infected individuals. Serum levels in normal HIV seronegative individuals were low, with a mean of 1.6 IL-6 U/ml as determined in the B9 assay. In contrast, serum IL-6 levels were significantly (p less than 0.01) elevated in 30 HIV seropositive individuals. Stage 1 and 2 (W.R. classification) patients (10 studied) had a mean of 25 IL-6 U/ml; stage 3 and 4 patients (10 studied) had a mean of 46 IL-6 U/ml; and stage 5 and 6 patients (10 studied) had a mean of 27 IL-6 U/ml. High levels of serum IL-6 correlated directly with levels of serum IgG, but did not correlate with serum levels of circulating soluble IL-2. Since IL-6 is known to induce B cell growth and differentiation but not to induce IL-2 production in mitogen-activated T cells, these findings suggest the possibility that infection in vivo with HIV induces IL-6 secretion by monocytes. Endogenously produced IL-6 may be responsible for high IgG levels in HIV-infected individuals.